This invention describes an improved, commercializable process for the synthesis of certain useful azapirone compounds. "Azapirone" is a term that has been used to describe a structural class of psychotropic compounds that demonstrate similar pharmacology relating to interaction with monoaminergic pathways in particular brain regions.
The azapirones amenable to the new process of this invention can be shown by some representative illustrations of certain azapirone drug agents having structural formula (I). ##STR1##
Perhaps the best known representative of the azapirone class of psychotropic agents is buspirone (1), originally disclosed in U.S. Pat. No. 3,717,634. ##STR2##
Some other well known members are:
gepirone, where Z is ##STR3## (U.S. Pat. No. 4,423,049); tandospirone, where Z is ##STR4## (U.S. Pat. No. 4,507,303); and WY-47,846, where Z is ##STR5## (U.S. Pat. No. 4,892,943).
While a number of synthetic processes have been disclosed for the synthesis of these azapirones, a method of choice, currently used for large scale preparation of buspirone, was disclosed by Sims in U.S. Pat. No. 4,351,939. The Sims method involves the reaction of a spiro-substituted glutarimide (3) with a novel spiroquaternary ammonium halide (4) to yield buspirone or ##STR6## a close analog. The halide, X, is preferably bromide. The reaction is carried out in a hot inert reaction medium in the presence of a strong base. In practice, the reaction process involves a biphasic reaction of (3) and (4) in refluxing xylene with solid potassium carbonate.
For scale-up, this prior art synthesis suffers from several processing disadvantages including high temperature processing of toxic solvents, a biphasic reaction mixture requiring highly efficient stirring, and the presence of inorganic by-products.
In contrast, the improved process proceeds via an imidate salt, free of inorganic by-products, and convertible in high yield to the desired azapirone upon gentle heating. There is nothing in the Sims process or other background art that would suggest the novel process and imidate salt intermediates of the present invention.